DIADS-3: A randomized double-blind, placebo-controlled trial of venlafaxine for depression in Alzheimer's Disease Alzheimer's disease (AD) is a growing health problem currently affecting 5.3 million persons in the U.S., a number that is estimated to triple by 2050. Neuropsychiatric symptoms are near-universal in AD and are a major contributor to patient and caregiver distress. One of the most prominent and distressing neuropsychiatric symptoms is depression, affecting up to 50% of patients with AD. There is currently no pharmacologic or non-pharmacologic intervention proven to be effective in depression of AD (dAD), and we have recently published results from a hypothesis-testing randomized controlled trial (RCT) of sertraline for dAD which showed no drug effect. Thus, there is a great need for development of new treatments for dAD. Most of the prior trials have studied serotonin-selective reuptake inhibitors, but there is considerable for the involvement of noradrenaline (NA) as well as serotonin (5-HT) in brain mechanisms underlying depression and AD. Thus, serotonin-noradrenaline reuptake inhibitors (SNRIs) are attractive alternatives for treatment of dAD. To date there are no SNRI RCTs in dAD with adequate dosing for SNRI effect and adequate duration to detect lasting changes in mood outcomes;the one RCT of venlafaxine is underdosed (at a dose with only SSRI effect) and too brief to adequately assess mood outcomes (6 weeks). Thus, we propose DIADS-3: a proof-of-concept RCT of venlafaxine for dAD. 64 participants with dAD will be randomized to Effexor XR (target dose of 225 mg daily) vs. placebo for 12 weeks'double-blind randomized treatment. The trial will be conducted at Johns Hopkins University by a highly experienced AD trials team that has recruited >800 participants for trials since 2004. Primary outcomes at 12 weeks are 1) rates of response on the modified AD Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC);2) rates of remission defined as a Cornell Scale for Depression in Dementia (CSDD) score d6 PLUS a mADCS-CGIC d2;3) CSDD scores on CSDD. Secondary outcomes will include safety assessments and examination of the association of serum venlaxine + metabolite levels with response. Data analyses will be on an intent-to-treat basis, and multiple imputation will be utilized as appropriate for missing data. DIADS-3 has the potential to significantly impact on treatment of dAD and, if drug effect is observed, to lead to a definitive hypothesis- testing trial of venlafaxine for dAD. PUBLIC HEALTH RELEVANCE: Depression in Alzheimer's disease is a major cause of distress for patients and caregivers, and there is no proven treatment to date. DIADS-3 offers the possibility of developing a new form of drug treatment for depression in Alzheimer's disease and thus improving the quality of life of patients and caregivers alike.